The present invention relates to a coated so active drug composition having releasability of the active drug in the small or large intestine or, more particularly, to a coated solid fibrinogen receptor antagonist composition which, when orally administered, passes unaffected through the stomach but is disintegrated when it reaches the small or large intestine so as to release the therapeutically active drug contained therein only in the small or large intestine.
Platelet activation and aggregation are involved in unstable angina and acute myocardial infarction, in reocclusion following thrombolytic therapy and angioplasty, in transient ischemic attacks and in a variety of other vaso-occlusive disorders. When a blood vessel is damaged either by acute intervention such as angioplasty, or, more chronically, by the pathophysiological processes of atherosclerosis, platelets are activated to adhere to the disrupted surface and to each other. This activation, adherence and aggregation may lead to occlusive thrombus formation in the lumen of the blood vessel.
Antiplatelet therapy has been used in a wide variety of cardiovascular disease states and in conjunction with interventional therapy such as coronary artery or peripheral bypass grafting, cardiac valve replacement, and percutaneous transluminal coronary angioplasty (PTCA). Available drugs, such as aspirin and ticlopidine, have shown efficacy in syndromes involving vascular occlusion, presumably due to sustained inhibition of platelet function. However, the inhibitory effects of aspirin and ticlopidine are dependent upon the agonist which activates the platelet. For example, aspirin is effective in blocking platelet aggregation induced by agonists such as collagen that are dependent upon the cylooxygenase pathway. It is, however, less effective against concentrations of thrombin which can act by cyclooxygenase independent pathways. Likewise, ticlopidine's inhibitory effects can be overcome by combinations of agonists. Thus, an efficacious inhibitor of platelet aggregation that acts independently of the agonist and the pathway activating the platelet could be an important therapeutic advance providing greater efficacy than aspirin or ticlopidine in a broader spectrum of thrombotic events.
The final obligatory step in platelet aggregation is the binding of fibrinogen to an activated membrane-bound glycoprotein complex, GP IIb/IIIa (.alpha..sub.II .beta..sub.3). Platelet activators such as thrombin, collagen, epinephrine or ADP, are generated as an outgrowth of tissue damage. During activation, GP IIb/IIIa undergoes changes in conformation that results in exposure of occult binding sites for fibrinogen. There are six putative recognition sites within fibrinogen for GP IIb/IIIa and thus fibrinogen can potentially act as a hexavalent ligand to crossing GP IIb/IIIa molecules on adjacent platelets. A deficiency in either fibrinogen or GP IIb/IIIa prevents normal platelet aggregation regardless of the agonist used to activate the platelets. Since the binding of fibrinogen to its platelet receptor is an obligatory component of normal aggregation, GP IIb/IIIa is an attractive target for an antithrombotic agent.
Orally active agents include SC54684, which is a prodrug (i.e., it requires biotransformation in vivo to its active form) with high oral bioavailability and RO43-8857, GR144053, and DMP728, which are themselves the active inhibitors (Cook et al. ibid.; and Cox et al. ibid.). Literally thousands of other compounds have been synthesized in an attempt to obtain optimal potency, metabolic stability, receptor specificity, and favorable intravascular survival. Despite variations in these compounds, virtually all of them retain the basic charge relations of the RGD sequence with a positive charge separated from a negative charge by approximately 10-20 .ANG. (Cook et al. ibid.; and Cox et al. ibid.). Acad. ibid.).
Oral fibrinogen receptor antagonists are readily absorbed when a patient consumes them on an empty stomach. However, it has been recently observed that absorption and bioavailability of oral fibrinogen receptor antagonists, when taken with food, may be reduced by the presence of food in the stomach.
Food is digested in the stomach, by mixing with digestive aids such as secreted acid and digestive enzymes, to form a material referred to as chyme. Chyme is a thick semifluid mass of partly digested food that is passed from the stomach to the duodenum
The present invention provides a means for allowing the active drug to remain in the stomach in the presence of food. By this means, food is converted in the stomach to chyme and emptied into the duodenum prior to transfer of the active drug into the duodenum. The active drug is transferred to the duodenum only after food has first been converted into chyme and passed into the duodenum. The active drug is thus released in the intestine following food digestion, thereby preventing food interaction.